scholarly journals 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Mathias Gorski ◽  
Peter J. van der Most ◽  
Alexander Teumer ◽  
Audrey Y. Chu ◽  
Man Li ◽  
...  
Keyword(s):  
Kidney Function ◽  
Kidney Development ◽  
Association Studies ◽  
Meta Analysis ◽  
European Ancestry ◽  
P Value ◽  
Genome Wide Association Studies ◽  
1000 Genomes ◽  
Gene Sets ◽  
Project Promise

Abstract HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

scholarly journals Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

2017 ◽  
Vol 16 (11) ◽  
pp. 898-907 ◽  
Author(s):  
Barbara Schormair ◽  
Chen Zhao ◽  
Steven Bell ◽  
Erik Tilch ◽  
Aaro V Salminen ◽  
...  
Keyword(s):  
Restless Legs Syndrome ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Restless Legs ◽  
Genome Wide

Trans-Ethnic Meta-Analysis of Interactions Between Genetics and Early-Life Socioeconomic Context on Memory Performance and Decline in Older Americans

2021 ◽  
Author(s):  
Jessica D Faul ◽  
Minjung Kho ◽  
Wei Zhao ◽  
Kalee E Rumfelt ◽  
Miao Yu ◽  
...  
Keyword(s):  
Parental Education ◽  
Association Studies ◽  
Memory Performance ◽  
Meta Analysis ◽  
African Ancestry ◽  
Later Life ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Multiple Testing Correction ◽  
Socioeconomic Context

Abstract Background Later-life cognitive function is influenced by genetics as well as early- and later-life socioeconomic context. However, few studies have examined the interaction between genetics and early childhood factors. Methods Using gene-based tests (interaction sequence kernel association test [iSKAT]/iSKAT optimal unified test), we examined whether common and/or rare exonic variants in 39 gene regions previously associated with cognitive performance, dementia, and related traits had an interaction with childhood socioeconomic context (parental education and financial strain) on memory performance or decline in European ancestry (EA, N = 10 468) and African ancestry (AA, N = 2 252) participants from the Health and Retirement Study. Results Of the 39 genes, 22 in EA and 19 in AA had nominally significant interactions with at least one childhood socioeconomic measure on memory performance and/or decline; however, all but one (father’s education by solute carrier family 24 member 4 [SLC24A4] in AA) were not significant after multiple testing correction (false discovery rate [FDR] &lt; .05). In trans-ethnic meta-analysis, 2 genes interacted with childhood socioeconomic context (FDR &lt; .05): mother’s education by membrane-spanning 4-domains A4A (MS4A4A) on memory performance, and father’s education by SLC24A4 on memory decline. Both interactions remained significant (p &lt; .05) after adjusting for respondent’s own educational attainment, apolipoprotein-ε4 allele (APOE ε4) status, lifestyle factors, body mass index, and comorbidities. For both interactions in EA and AA, the genetic effect was stronger in participants with low parental education. Conclusions Examination of common and rare variants in genes discovered through genome-wide association studies shows that childhood context may interact with key gene regions to jointly impact later-life memory function and decline. Genetic effects may be more salient for those with lower childhood socioeconomic status.

scholarly journals Genome-Wide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy

2020 ◽  
Author(s):  
Katherina C. Chua ◽  
Chenling Xiong ◽  
Carol Ho ◽  
Taisei Mushiroda ◽  
Chen Jiang ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Association Studies ◽  
Meta Analysis ◽  
Regulatory Elements ◽  
Hazard Ratio ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Sensory Peripheral Neuropathy ◽  
Genome Wide ◽  
Microtubule Targeting Agents

AbstractMicrotubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1; e.g., rs74497159, βCALGB40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 - 0.928), βCALGB40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 - 1.053); PMETA = 3.62×10−7) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.

scholarly journals Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry

2018 ◽  
Vol 28 (1) ◽  
pp. 166-174 ◽  
Author(s):  
Sara L Pulit ◽  
Charli Stoneman ◽  
Andrew P Morris ◽  
Andrew R Wood ◽  
Craig A Glastonbury ◽  
...  
Keyword(s):  
Body Fat ◽  
Association Studies ◽  
Meta Analysis ◽  
Fat Distribution ◽  
Body Fat Distribution ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

Abstract More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

Abstract P260: Large-scale Meta-analysis of Diverse Ancestry Genome-wide Association Studies to Identify Pharmacogenomic Interactions of Sulfonylureas and ECG Phenotypes

Circulation ◽  
2016 ◽  
Vol 133 (suppl_1) ◽  
Author(s):  
James S Floyd ◽  
Colleen Sitlani ◽  
Christy L Avery ◽  
Eric A Whitsel ◽  
Leslie Lange ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Qt Interval ◽  
Association Studies ◽  
Meta Analysis ◽  
Small Sample ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Meta Analyses

Introduction: Sulfonylureas are a commonly-used class of diabetes medication that can prolong the QT-interval, which is a leading cause of drug withdrawals from the market given the possible risk of life-threatening arrhythmias. Previously, we conducted a meta-analysis of genome-wide association studies of sulfonylurea-genetic interactions on QT interval among 9 European-ancestry (EA) cohorts using cross-sectional data, with null results. To improve our power to identify novel drug-gene interactions, we have included repeated measures of medication use and QT interval and expanded our study to include several additional cohorts, including African-American (AA) and Hispanic-ancestry (HA) cohorts with a high prevalence of sulfonylurea use. To identify potentially differential effects on cardiac depolarization and repolarization, we have also added two phenotypes - the JT and QRS intervals, which together comprise the QT interval. Hypothesis: The use of repeated measures and expansion of our meta-analysis to include diverse ancestry populations will allow us to identify novel pharmacogenomic interactions for sulfonylureas on the ECG phenotypes QT, JT, and QRS. Methods: Cohorts with unrelated individuals used generalized estimating equations to estimate interactions; cohorts with related individuals used mixed effect models clustered on family. For each ECG phenotype (QT, JT, QRS), we conducted ancestry-specific (EA, AA, HA) inverse variance weighted meta-analyses using standard errors based on the t-distribution to correct for small sample inflation in the test statistic. Ancestry-specific summary estimates were combined using MANTRA, an analytic method that accounts for differences in local linkage disequilibrium between ethnic groups. Results: Our study included 65,997 participants from 21 cohorts, including 4,020 (6%) sulfonylurea users, a substantial increase from the 26,986 participants and 846 sulfonylureas users in the previous meta-analysis. Preliminary ancestry-specific meta-analyses have identified genome-wide significant associations (P < 5х10–8) for each ECG phenotype, and analyses with MANTRA are in progress. Conclusions: In the setting of the largest collection of pharmacogenomic studies to date, we used repeated measurements and leveraged diverse ancestry populations to identify new pharmacogenomic loci for ECG traits associated with cardiovascular risk.

scholarly journals Genome-Wide Association Study Identifies Loci Associated with Sensitive Skin

Cosmetics ◽  
2020 ◽  
Vol 7 (2) ◽  
pp. 49
Author(s):  
Miranda A. Farage ◽  
Yunxuan Jiang ◽  
Jay P. Tiesman ◽  
Pierre Fontanillas ◽  
Rosemarie Osborne
Keyword(s):  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
European Ancestry ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Online Questionnaire ◽  
Sensitive Skin ◽  
Genome Wide ◽  
Skin Conditions

Individuals suffering from sensitive skin often have other skin conditions and/or diseases, such as fair skin, freckles, rosacea, or atopic dermatitis. Genome-wide association studies (GWAS) have been performed for some of these conditions, but not for sensitive skin. In this study, a total of 23,426 unrelated participants of European ancestry from the 23andMe database were evaluated for self-declared sensitive skin, other skin conditions, and diseases using an online questionnaire format. Responders were separated into two groups: those who declared they had sensitive skin (n = 8971) and those who declared their skin was not sensitive (controls, n = 14,455). A GWAS of sensitive skin individuals identified three genome-wide significance loci (p-value < 5 × 10−8) and seven suggestive loci (p-value < 1 × 10−6). Of the three most significant loci, all have been associated with pigmentation and two have been associated with acne.

scholarly journals A meta-analysis of the genome-wide association studies on two genetically correlated phenotypes (self-reported headache and self-reported migraine) identifies four new risk loci for headaches (N=397,385)

2021 ◽  
Author(s):  
Weihua Meng ◽  
Parminder Reel ◽  
Charvi Nangia ◽  
Aravind Rajendrakumar ◽  
Harry Hebert ◽  
...  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
The Self ◽  
Genome Wide Association ◽  
P Value ◽  
Clinical Settings ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Genetic Mechanisms ◽  
The Uk

Headache is one of the commonest complaints that doctors need to address in clinical settings. The genetic mechanisms of different types of headache are not well understood. In this study, we performed a meta-analysis of genome-wide association studies (GWAS) on the self-reported headache phenotype from the UK Biobank cohort and the self-reported migraine phenotype from the 23andMe resource using the metaUSAT for genetically correlated phenotypes (N=397,385). We identified 38 loci for headaches, of which 34 loci have been reported before and 4 loci were newly identified. The LRP1-STAT6-SDR9C7 region in chromosome 12 was the most significantly associated locus with a leading P value of 1.24 x 10-62 of rs11172113. The ONECUT2 gene locus in chromosome 18 was the strongest signal among the 4 new loci with a P value of 1.29 x 10-9 of rs673939. Our study demonstrated that the genetically correlated phenotypes of self-reported headache and self-reported migraine can be meta-analysed together in theory and in practice to boost study power to identify more new variants for headaches. This study has paved way for a large GWAS meta-analysis study involving cohorts of different, though genetically correlated headache phenotypes.

scholarly journals Identification of type 2 diabetes loci in 433,540 East Asian individuals

2019 ◽  
Author(s):  
Cassandra N Spracklen ◽  
Momoko Horikoshi ◽  
Young Jin Kim ◽  
Kuang Lin ◽  
Fiona Bragg ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Association Studies ◽  
Meta Analysis ◽  
East Asian ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
European Populations

SUMMARYMeta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

scholarly journals Meta-analysis of genome-wide association studies for height and body mass index in ∼700000 individuals of European ancestry

2018 ◽  
Vol 27 (20) ◽  
pp. 3641-3649 ◽  
Author(s):  
Loic Yengo ◽  
Julia Sidorenko ◽  
Kathryn E Kemper ◽  
Zhili Zheng ◽  
Andrew R Wood ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract 56: Genome-wide Association Studies of Incident Stroke: The Charge Consortium

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Stephanie Debette ◽  
Ganesh Chauhan ◽  
Audrey Chu ◽  
Myriam Fornage ◽  
Josh C Bis ◽  
...  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Acute Stage ◽  
Genome Wide Association ◽  
Population Substructure ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Large Artery ◽  
Aging Research ◽  
Genome Wide

Background: Despite a high heritability, only few stroke risk genes are known. Genetic association studies performed in a hospital-based setting may fail to detect genes modulating both stroke susceptibility and severity, given early deaths at the acute stage. This selection bias is avoided when studying incident stroke in a population-based setting. Methods: We conducted a meta-analysis of genome-wide association studies of incident stroke in 11 community-based longitudinal studies from the Cohorts of Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Genome-wide Cox regressions were performed adjusting for age, gender and population substructure, using 1000GpIv3 imputed genotypes. Results were combined using inverse variance weighted meta-analysis. Results: The study sample comprised 65,204 participants (71.5% women) of European ancestry, aged 66.2±8.0 years at DNA draw, followed up for 10.8±3.8 years. In 11 studies, 3,389 participants developed incident stroke, and in 8 studies, 2,223 developed incident ischemic stroke (IS): 531 cardioembolic [CE] and 1,576 atherothrombotic [AT]. The most significant association with incident stroke was for a novel variant on chr9p23 (MAF=0.35), HR=1.15 [95%CI:1.09[[Unable to Display Character: &#8210;]]1.21], p=8.5х10-8: p=2.54x10-5 for IS; 1.19x10-4, AT-IS; and 0.019, CE-IS. Associations were in the same direction for all participating studies, and 5 additional SNPs in this locus reached p<10-6. The most significant association with incident IS was for rs11833579 [NINJ2], HR=1.21[1.13[[Unable to Display Character: &#8210;]]1.30], p=2.1х10-7, but p-random-effects=9.54x10-3 (p-heterogeneity=0.02, I2=57.9%). We replicated published associations for CE-IS (rs6843082-G [PITX2], HR=1.30[1.13-1.49], p=1.95x10-4) and for large artery stroke with AT-IS (rs2107595-A [HDAC9], HR=1.13[1.03[[Unable to Display Character: &#8210;]]1.24], p=0.012) Conclusion: In the largest GWAS of incident stroke, we detected one novel association with all stroke, requiring confirmation in independent samples. Expansion of the discovery sample and replication of findings are planned in the coming months. Detecting genetic variants associated with incident stroke may provide important clues for understanding pathways involved in stroke susceptibility and tolerance to acute vascular brain injury.

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